Apogossypolone Inhibits Cell Growth by Inducing Cell Cycle Arrest in U937 Cells

Oncol Rep. 2009 Jul;22(1):193-8. doi: 10.3892/or_00000424.

Abstract

We examined the effect of apogossypolone (ApoG2), a new derivative from gossypol on cell cycle regulation in U937 human leukemic monocyte lymphoma cells in vitro. ApoG2 decreased the viability of U937 cells by inducing G1 arrest followed by apoptosis in a dose-dependent manner. The G0/G1 phase of the cell cycle is regulated by cyclin-dependent kinases (Cdk), cyclins and cyclin-dependent kinase inhibitors (Cdki). We show by western blot analysis, that the ApoG2-induced G1 arrest was mediated through the increased expression of Cdki proteins (p21cip1/waf1) with a simultaneous decrease in cdk2, cdk4, cyclin D1 and cyclin E expression. The induction of apoptosis after treatment with ApoG2 for 12, 24 and 48 h was demonstrated by flow cytometry analysis. ApoG2 also induced cytochrome c release and activation of caspase-3. To our knowledge, this is the first time that ApoG2 has been reported to potently inhibit the proliferation of human monocytic lymphoma U937 cells through G1 arrest. These findings suggest that ApoG2 may be a potential chemotherapeutic agent for the treatment of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Cycle / drug effects*
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cyclin D1 / metabolism
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cytochromes c / metabolism
  • Dose-Response Relationship, Drug
  • Gossypol / analogs & derivatives*
  • Gossypol / pharmacology
  • Humans
  • Lymphoma / metabolism
  • Lymphoma / pathology*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Time Factors
  • U937 Cells

Substances

  • Antineoplastic Agents
  • CCND1 protein, human
  • CDKN1A protein, human
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p21
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • apogossypolone
  • Cyclin D1
  • Cytochromes c
  • CDK2 protein, human
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • CASP3 protein, human
  • Caspase 3
  • Gossypol